Suppression of cdc42 activity could be a promising therapy for nephrotic syndrome

A group led by the Department of Cell Biology at the Kidney Research Center, Niigata University revealed that elevated activity of cdc42 is a critical initiation event leading to proteinuria, and proposed that suppression of cdc42 activity could be a promising therapy for nephrotic syndrome.

Glomerulus is a filtration unit of the kidney, and the glomerular capillary wall functions as a barrier, preventing the leak of plasma protein into urine. Proteinuria is a clinical symptom showing dysfunction of the barrier of glomerular capillary wall, and is an aggravating factor leading to kidney failure. Besides, proteinuria is reported to be a risk factor for cardiovascular and cerebrovascular diseases. Glomerular epithelial cell (podocyte) is located in outer layer of glomerular capillary wall, and possesses unique processes named foot processes. Neighboring foot processes are bridged by slit diaphragm. It is accepted that slit diaphragm functions as a final barrier preventing proteinuria. Recent clinical studies reported that the major parts of nephrotic syndrome are caused by autoantibody against nephrin, a key component of slit diaphragm.

A group at Niigata University analyzed signaling pathways in podocyte after stimulation by anti-nephrin antibody. The study revealed that ephrin-B1 at slit diaphragm interacted with nephrin and Par6, and that the anti-nephrin antibody caused the phosphorylations of nephrin and ephrin-B1 in a Ca²⁺ influx–dependent manner. Phosphorylated ephrin-B1 was dissociated from nephrin and also from Par6, and Par6 came to interact with cdc42. The binding of Par6 promoted cdc42 activity. Elevated cdc42 activity promoted calcineurin activity, activated Snail, a transcription factor, and decreased mRNA expression of nephrin, ephrin-B1 and other functional molecules of slit diaphragm (cf. Image). The altered expression of the functional molecules induced the loss of barrier function of slit diaphragm, which leads to proteinuria. The study also showed that a cdc42 inhibitor restored the expression of slit diaphragm functional molecules. Researchers argued that the regulation of cdc42 activity could be a promising therapy for nephrotic syndrome.